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Review
. 2015:2015:957248.
doi: 10.1155/2015/957248. Epub 2015 Oct 26.

Therapeutic Actions of the Thiazolidinediones in Alzheimer's Disease

María José Pérez  1 , Rodrigo A Quintanilla  2
Affiliations
Review

Therapeutic Actions of the Thiazolidinediones in Alzheimer's Disease

María José Pérez et al. PPAR Res. 2015.

Abstract

Alzheimer's disease (AD) is a multifactorial metabolic brain disorder characterized by protein aggregates, synaptic failure, and cognitive impairment. In the AD brain is common to observe the accumulation of senile plaques formed by amyloid-beta (Aβ) peptide and the neurofibrillary tangles composed of modified tau protein, which both lead to cellular damage and progressive neurodegeneration. Currently, there is no effective therapy for AD; however several studies have shown that the treatments with the peroxisome proliferators activated receptor-gamma (PPARγ) agonists known as thiazolidinedione drugs (TZDs), like rosiglitazone and pioglitazone, attenuate neurodegeneration and improve cognition in mouse models and patients with mild-to-moderate AD. Furthermore, studies on animal models have shown that TZDs inhibit neuroinflammation, facilitate amyloid-β plaque clearance, enhance mitochondrial function, improve synaptic plasticity, and, more recently, attenuate tau hyperphosphorylation. How TZDs may improve or reduce these pathologic signs of AD and what the mechanisms and the implicated pathways in which these drugs work are are questions that remain to be answered. However, in this review, we will discuss several cellular targets, in which TZDs can be acting against the neurodegeneration.

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Figures

Figure 1
Figure 1
Targets of thiazolidinediones drugs in Alzheimer's disease. The TZDs can bind to PPARγ receptors and other pathways that regulate energy metabolism, in cellular and animal models of AD. In cognition and behavioral test, these drugs increase the memory performance of the animals and also decrease the Aβ deposits accelerating the amyloid plaque clearance. At more cellular levels, TZDs promote the neuronal survival, differentiation, and synaptic plasticity and also increase the phagocytosis and reduce neuroinflammation both in astrocytes and in microglia. In the mitochondria, TZDs induce biogenesis and enhance the mitochondrial function observed by a rise in the respiratory complex activities and reduction of the oxidative stress. Finally, TZDs are capable of reducing tau phosphorylation through the inhibition of different kinases activities and the later formation of the neurofibrillary tangles presented in AD.
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